The effect of obesogenic and inflammatory factors in regulating adipocytes lipid chaperone proteins

Mohd Radzuan, Hazulin (2020) The effect of obesogenic and inflammatory factors in regulating adipocytes lipid chaperone proteins. PhD thesis, University of Nottingham.

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Abstract

It has been increasingly clear that adipose tissue (AT) actively secretes lipid chaperone proteins (LCPs) into circulatory system without preceding tissue injury or cell death event. Among them are fatty acid binding protein 4 (FABP4), which is known to be increased in inflammatory condition despite of absence of any secretion directed signals; and lipocalin2 (LCN2), which function is still debatable since there are evidences supporting its role in both pro and anti-inflammatory states.

This study intended to investigate (i)regulation of adipocyte derived LCPs in response towards various cellular environment states (e.g. hyperglycaemia and hypoxia), (ii)changes in LCN2 and FABP4 signalling as a result of calcium flux, mediated by transient receptor potential vanilloid 4 (TRPV4) ligands; and iii)interaction effect of multiple cellular factors upon adipocyte genes expression. These experiments involved cells treated in normal glucose media (NG), supplemented with 5.5mMol/l glucose; and high glucose media (HG), supplemented with 17.7mMol/l glucose.

Initially, this study showed cells that were given aforementioned media, displayed similar morphological appearance and cells viability in all groups. When concomitant obesogenic factors were applied, such as HG and hypoxia, LCN2 secretion mainly upregulated by the former factor, while FABP4 secretion was induced by the latter. Apart from these two factors, duration of adipogenesis also play a role in regulating LCN2 and FABP4, since the former was released abundantly at early stage of adipogenesis and the latter was secreted by mature adipocytes.

Next, this study reported downregulation of LCN2 attributed by GSK101, a potent TRPV4 agonist, which manifests as pro inflammatory mediator. Whereas inhibition of TRPV4 channel by HC067 caused reduction in FABP4 signalling. Chemical activation of TRPV4 channel may compromise adipocytes differentiation as evidence by reduced expression of pparγ and pgc1α. It is also presumed to induce inflammatory response due to high expression of ccl2 in cells treated with GSK101.

Hence, the interaction of main effects of HG and TRPV4 treatments showed that these 2 factors concomitantly affects the regulation of LCN2. However, the latter was the main factor that influenced adipocyte genes expression such as fabp4 and pparγ. Therefore, verifying the regulatory mechanism and interaction of factors that modify adipocyte-derived LCPs signalling could help us to understand its role in inflammatory response, whether it will further promote or suppress development of metabolic diseases.

We hypothesize that nuclear factor of activated T cell (NFAT) presumably play a role, either direct or indirectly, via an as yet unidentified mechanism in LCN2 and FABP4 regulation. Thus, extended research is required to further explore the means.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Bennett, Andrew
Keywords: Adipose tissue; Lipid chaperone proteins; Fatty acid binding protein 4; lipocalin2; Inflammatory response; Adipocytes
Subjects: Q Science > QP Physiology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID: 59800
Depositing User: Mohd Radzuan, Hazulin
Date Deposited: 10 Jun 2020 10:33
Last Modified: 10 Jun 2020 10:33
URI: http://eprints.nottingham.ac.uk/id/eprint/59800

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